PROJECT SUMMARY: Survival rates in patients with oral cavity tumors have remained nearly stagnant in the past decade with exceptional morbidity e.g., tongue cancers. The goal of this Academic-Industry Partnership (AIP) application is to develop, for the first time, a single theranostic agent namely targeted Dual Function Antibody Conjugate (DFAC) amenable to deep tissue photoacoustic imaging (PAI) with targeted photodynamic therapy (PDT), and an integrated PAI-ultrasound imaging (USI) module for surgery guidance such that the two main barriers to oral cancer treatment outcomes are overcome. Difficulty in gauging the depth of tumor invasion during surgical resection and residual microscopic disease are the two main barriers responsible for the high loco-regional recurrence rates in oral cavity tumors. Cautionary removal of extra normal tissue leads to functional loss and a compromised quality of life. Through this AIP, we establish a collaborative framework between the academic research lab of Dr. Hasan at Massachusetts General Hospital (MGH), the clinical Otolaryngology surgical team of Drs. Varvares and August at Mass Eye and Ear Infirmary and MGH, and the Akita Innovations industry team, to create a comprehensive theranostic solution that enables deep tissue image-guided, normal tissue-sparing surgery and tumor-targeted spatially-localized therapy in the oral cavity. Our synergistic scientific expertise, respective infrastructures, clinical translation experience and geographic proximity position us well to achieve our goals. The proposal has 3 parts that will enable deep tissue image-guided surgery and treat residual disease in one intraoperative setting. 1. A DFAC, that enables both imaging and therapy by targeting Epidermal growth factor receptor (EGFR), an established biomarker in oral cavity tumors, 2. A custom-built, PAI integrated clinical USI module for surgical guidance. 3. Targeted PDT. DFAC is composed of cetuximab, an FDA-approved EGFR targeting antibody, conjugated to a new near-infrared (>850 nm) napthalocyanine dye for deep-tissue PAI and an FDA-approved photosensitizer Benzoporphyrin Derivative (BPD). We postulate that DFAC-enabled deep-tissue PAI- guided surgery and intraoperative PDT of residual disease will achieve local tumor control, reduce recurrence, increase disease-free survival and improve quality of life in oral cancer patients. The concept will be validated pre-clinically and clinically in 4 specific aims: Aim-1 Development and in vitro optimization of DFACs for photoacoustic contrast and therapeutic efficacy. Optimize clinical intra-oral USI systems to PAI via customized light delivery strategies and spectroscopic algorithms. Aim-2. Perform rodent toxicology studies, GMP production of DFAC and obtain eIND approvals. Aim-3. Evaluation of therapeutic efficacy in mouse models of oral cancer. Aim-4. Implementation of first-in-human Phase 0 clinical trial with DFAC-guided PAI ability to delineate deep tumor margins. Relevance: The study offers deep tissue imaging and targeted therapy in a single intraoperative session, resulting in lower recurrence, lower cost, higher overall survival and improved quality of life. The modular design of DFAC and integrated PAI-US, enables adaptation of the platform to other cancers.